Crasentan sodium injection and preparation method thereof

Abstract

The invention relates to the technical field of medicines, and particularly discloses a clasentan sodium injection and a preparation method thereof. The clasentan sodium injection is prepared from the following raw materials in parts by weight: 180 to 220 parts of clasentan sodium, 10 to 25 parts of an antioxidant, 3 to 8 parts of an osmotic pressure regulator, 400 to 500 parts of a cosolvent and the balance of water for injection, by adding a proper amount of the antioxidant and the osmotic pressure regulator into the raw materials of the clasentan sodium injection, the phenomenon of oxidative damage of the clasentan sodium is reduced, and the bioavailability and the stability of the clasentan sodium injection are improved.

Description

Technical Field

[0001] The present application relates to the field of medical technology, and in particular to a clasentan sodium injection and a preparation method thereof. Background Art

[0002] Cerebral vasospasm (CVS) is a common high-risk complication of aneurysmal subarachnoid hemorrhage (aSAH), which can cause delayed ischemic injury, secondary cerebral infarction and other adverse consequences. Clazosentan is an endothelin receptor antagonist that has been shown to have significant effects in preventing cerebral vasospasm and its related symptoms after aneurysmal subarachnoid hemorrhage (aSAH).

[0003] In pharmaceutical preparations, clazotin sodium usually exists in the form of salt, which can improve solubility and bioavailability in aqueous media. However, clazotin sodium is unstable in aqueous solutions and is easily degraded, especially under the conditions of light and oxygen, which can produce impurities and affect the safety of the drug. Summary of the invention

[0004] In order to improve the stability of clasentan sodium injection, the present application provides a clasentan sodium injection and a preparation method thereof.

[0005] In a first aspect, the present application provides a clasentan sodium injection, which adopts the following technical solution: A clazotin sodium injection comprises the following raw materials in parts by weight: 180-220 parts of clazotin sodium, 10-25 parts of an antioxidant, 3-8 parts of an osmotic pressure regulator, 400-500 parts of a cosolvent, and the remainder being water for injection.

[0006] By adopting the above technical solution, adding an appropriate amount of antioxidant to the raw material of clasentan sodium injection can protect clasentan sodium from oxidative damage by removing free radicals or inhibiting oxidation reactions, thereby improving the stability of the active components in clasentan sodium injection. The osmotic pressure regulator is used to adjust the osmotic pressure of the injection, which can make the clasentan sodium injection match the osmotic pressure of human body fluids, avoid osmotic pressure shock to cells during injection, and improve the bioavailability of clasentan sodium injection.

[0007] Preferably, the antioxidant is at least one of sodium thiosulfate, vitamin C and sodium sulfite.

[0008] By adopting the above technical scheme, sodium thiosulfate can effectively remove free radicals through sulfur atoms and prevent oxidation of active drug components. Clazolyl sodium injection is slightly alkaline. In an alkaline environment, sodium thiosulfate has good stability and can continuously provide antioxidant protection, thereby improving the stability and durability of Clazolyl sodium injection. Vitamin C can remove a variety of free radicals, including superoxide anions and hydroxyl radicals, and has a significant protective effect on the stability of drugs. Sodium sulfite releases sulfite ions, reacts with oxidants, consumes free radicals, and protects drugs from oxidation. Under alkaline conditions, sodium sulfite can continuously provide antioxidant protection and improve the stability of Clazolyl sodium injection.

[0009] Preferably, the osmotic pressure regulator is at least one of glucose, sodium chloride, phosphate or citrate.

[0010] By adopting the above technical scheme, glucose can not only adjust the osmotic pressure of clasentan sodium injection, so that clasentan sodium injection matches the osmotic pressure of human extracellular fluid, reduce the stimulation to blood vessels and tissues, but also provide patients with a certain amount of energy. Glucose can also be used as a carrier of clasentan sodium to enhance the dispersion and absorption effects of clasentan sodium. Sodium chloride can accurately adjust the osmotic pressure of clasentan sodium injection, so that clasentan sodium injection matches the osmotic pressure of human extracellular fluid. At the same time, sodium chloride has a low cost and is metabolically stable in the human body, and will not cause a significant metabolic burden. Phosphates and citrates can not only adjust the osmotic pressure of the injection, but also act as buffers to help maintain the pH value of clasentan sodium injection and improve the stability of clasentan sodium injection.

[0011] Preferably, the raw materials of the clasentan sodium injection also include 10-25 parts of an acid-base regulator and 5-12 parts of a stabilizer, and the acid-base regulator adjusts the pH of the clasentan sodium injection to 7-9.

[0012] By adopting the above technical solution, the pH of clasentan sodium injection is adjusted to 7-9, which can reduce the stimulation of clasentan sodium injection on blood vessels and tissues and improve the bioavailability of clasentan sodium injection. Using an acid-base regulator to adjust the pH of clasentan sodium injection to 7-9 can promote the stability of the drug during storage and use, reduce degradation caused by pH changes, and improve the stability of clasentan sodium injection.

[0013] Preferably, the acid-base regulator includes an acid regulator and a base regulator, the acid regulator is at least one of phosphoric acid, citric acid, tartaric acid, oxalic acid, and malic acid, and the base regulator is at least one of sodium phosphate, disodium hydrogen phosphate, sodium citrate, and sodium tartrate.

[0014] Preferably, the stabilizer is hydroxypropyl-β-cyclodextrin.

[0015] By adopting the above technical solution, hydroxypropyl-β-cyclodextrin can form an inclusion complex with the active components of the drug, thereby protecting the drug from the influence of the external environment and improving the chemical stability of the active components of clasentan sodium injection.

[0016] In the second aspect, the present application provides a method for preparing clasentan sodium injection, adopting the following technical scheme: a method for preparing clasentan sodium injection, comprising the following specific steps: mixing deoxygenated water for injection with clasentan sodium and a co-solvent, stirring evenly, then stirring evenly with an antioxidant and an osmotic pressure regulator, filtering using a composite filter membrane, and then filling and autoclaving to obtain clasentan sodium injection.

[0017] By adopting the above technical scheme, under the synergistic effect of various components, the active components in the prepared clasentan sodium injection have good stability and can be absorbed by the human body, reducing the impact on the human body and improving the bioavailability of the clasentan sodium injection.

[0018] Preferably, the deoxygenated water for injection is mixed with clasentan sodium and a cosolvent, stirred evenly, and then the antioxidant, osmotic pressure regulator, and stabilizer are stirred evenly to form a clasentan sodium mixture, and the pH of the clasentan sodium mixture is adjusted to 7-9 with an acid-base regulator, filtered with a composite filter membrane, and then filled and sterilized by hot pressure to obtain clasentan sodium injection.

[0019] Preferably, the composite filter membrane comprises a filter membrane with a pore size of 0.4-0.6 μm and a filter membrane with a pore size of 0.1-0.3 μm.

[0020] In summary, this application has the following beneficial effects: 1. Since the present application adopts the addition of an appropriate amount of antioxidants to the raw materials of clasentan sodium injection, clasentan sodium is protected from oxidative damage and the stability of the active components in clasentan sodium injection is improved. The osmotic pressure of the injection is adjusted by an osmotic pressure regulator to avoid osmotic pressure shock to cells during injection and improve the bioavailability of clasentan sodium injection.

[0021] 2. In this application, sodium thiosulfate, vitamin C and sodium sulfite are used as antioxidants to reduce the oxidation of active drug components. Clazolyl sodium injection is slightly alkaline. In an alkaline environment, antioxidants can maintain better stability, thereby improving the stability and durability of Clazolyl sodium injection. Glucose, sodium chloride, phosphate or citrate are used as osmotic pressure regulators to match the osmotic pressure of Clazolyl sodium injection with that of human extracellular fluid, reduce stimulation to blood vessels and tissues, and can also serve as a carrier of Clazolyl sodium to enhance the dispersion ability of Clazolyl sodium. Acid regulators and base regulators are used to adjust the pH of Clazolyl sodium injection to 7-9, reduce the degradation of active components caused by changes in pH, and improve the stability of Clazolyl sodium injection. DETAILED DESCRIPTION

[0022] The present application is further described in detail below in conjunction with embodiments.

[0023] All raw materials in the examples are commercially available. Example

[0024] Example 1 This embodiment provides a clasentan sodium injection, comprising the following raw materials in parts by weight: 200 g of clasentan sodium, 17 g of antioxidant, 5 g of osmotic pressure regulator, 450 g of cosolvent, and water for injection to make up to 10000 g, wherein the antioxidant is vitamin C, the osmotic pressure regulator is sodium chloride, and the cosolvent is propylene glycol.

[0025] The preparation method of clasentan sodium injection comprises the following specific steps: The deoxygenated water for injection is mixed with clasentan sodium and a cosolvent, stirred evenly, and then the antioxidant and the osmotic pressure regulator are stirred evenly, the volume is made up with water for injection, filtered through a filter membrane with a pore size of 0.5 μm and a filter membrane with a pore size of 0.2 μm in sequence, and then filled and sterilized at 121° C. to obtain clasentan sodium injection.

[0026] Example 2 The difference between Example 2 and Example 1 is that the amount of clasentan sodium used in the clasentan sodium injection raw material is 180g, the amount of antioxidant used is 10g, the amount of osmotic pressure regulator used is 3g, the amount of co-solvent used is 400g, and the water for injection is supplemented to 10000g.

[0027] Example 3 The difference between Example 3 and Example 1 is that the amount of clasentan sodium used in the clasentan sodium injection raw material is 220g, the amount of antioxidant used is 25g, the amount of osmotic pressure regulator used is 8g, the amount of co-solvent used is 500g, and the water for injection is supplemented to 10000g.

[0028] Example 4 The difference between Example 4 and Example 1 is that the antioxidant in the raw material of clasentan sodium injection is sodium thiosulfate.

[0029] Example 5 The difference between Example 5 and Example 1 is that the antioxidant in the raw material of clasentan sodium injection is a mixture of sodium thiosulfate and sodium sulfite, wherein the mass ratio of sodium thiosulfate to sodium sulfite is 1:1.

[0030] Example 6 The difference between Example 6 and Example 5 is that the osmotic pressure regulator in the raw material of clazotin sodium injection is a mixture of glucose and sodium chloride, and the mass ratio of glucose to sodium chloride is 1:1.

[0031] Example 7 The difference between Example 7 and Example 6 is that a clasentan sodium injection includes the following raw materials in parts by weight: 200 g of clasentan sodium, 17 g of antioxidant, 5 g of osmotic pressure regulator, 450 g of cosolvent, 17 g of acid-base regulator, and water for injection is supplemented to 10000 g. The acid-base regulator includes an acid regulator and an alkali regulator. The acid regulator is phosphoric acid, and the alkali regulator is disodium hydrogen phosphate.

[0032] The preparation method of clasentan sodium injection comprises the following specific steps: The deoxygenated water for injection is mixed with clasentan sodium and a cosolvent, and stirred evenly. Then, an antioxidant and an osmotic pressure regulator are stirred evenly. The volume is fixed with water for injection to form a clasentan sodium mixture. The pH of the clasentan sodium mixture is adjusted to 8 with an acid regulator and an alkali regulator. The mixture is filtered through a filter membrane with a pore size of 0.5 μm and a filter membrane with a pore size of 0.2 μm in turn, and then filled and sterilized at 121° C. to obtain clasentan sodium injection.

[0033] Example 8 The difference between Example 8 and Example 7 is that a clasentan sodium injection comprises the following raw materials in parts by weight: 200 g of clasentan sodium, 17 g of antioxidant, 5 g of osmotic pressure regulator, 450 g of cosolvent, 17 g of acid-base regulator, 9 g of stabilizer, and water for injection is added to 10,000 g, wherein the stabilizer is hydroxypropyl-β-cyclodextrin.

[0034] The preparation method of clasentan sodium injection comprises the following specific steps: The deoxygenated water for injection is mixed with clasentan sodium and a cosolvent, and stirred evenly. Then, an antioxidant, an osmotic pressure regulator and a stabilizer are stirred evenly. The volume is fixed with water for injection to form a clasentan sodium mixture. The pH of the clasentan sodium mixture is adjusted to 8 with an acid regulator and an alkali regulator. The mixture is filtered through a filter membrane with a pore size of 0.5 μm and a filter membrane with a pore size of 0.2 μm in turn, and then filled and sterilized at 121° C. to obtain clasentan sodium injection.

[0035] Example 9 The difference between Example 9 and Example 8 is that the amount of the acid-base regulator used in the raw material of clasentan sodium injection is 10 g, and the amount of the stabilizer used is 5 g.

[0036] Example 10 The difference between Example 10 and Example 8 is that the amount of the acid-base regulator used in the raw material of clasentan sodium injection is 25 g, and the amount of the stabilizer used is 12 g.

[0037] Comparative Example Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that no antioxidant is used in the raw materials of clasentan sodium injection.

[0038] Performance testing The following performance tests were performed on the clasentan sodium injection provided in Examples 1-10 of the present application and Comparative Example 1. The specific test results are shown in Table 1.

[0039] Detection Methods Content determination: The content of clasentan sodium injection was determined by high performance liquid chromatography.

[0040] Property observation: The clasentan sodium injection prepared in the present application was placed at 50° C. for 10 days, and the appearance changes of the clasentan sodium injection were observed.

[0041] Table 1: Performance test results data table Example Appearance Clarity content(%) Example 1 Clear liquid No foreign matter 99.5 Example 2 Clear liquid No foreign matter 99.3 Example 3 Clear liquid No foreign matter 99.4 Example 4 Clear liquid No foreign matter 99.5 Example 5 Clear liquid No foreign matter 99.6 Example 6 Clear liquid No foreign matter 99.65 Example 7 Clear liquid No foreign matter 99.7 Example 8 Clear liquid No foreign matter 99.8 Example 9 Clear liquid No foreign matter 99.75 Example 10 Clear liquid No foreign matter 99.79 Comparative Example 1 There is turbidity Turbid foreign matter appears 91.05 It can be seen from the performance test results that the clasentan sodium injection prepared in the present application has good stability and bioavailability under the synergistic effect of each component. The pH of the clasentan sodium injection is adjusted to neutral by an acid-base regulator, which can reduce the degradation of the injection caused by changes in pH. From the comparison between Comparative Example 1 and Example 1, it can be seen that by changing the components in the raw materials of the clasentan sodium injection of the present application and not using an antioxidant, the content and stability of the clasentan sodium injection are significantly reduced, and degradation may have occurred.

[0042] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed. However, as long as it is within the scope of the claims of the present application, it shall be protected by the patent law.

Claims

1. A clasentan sodium injection, characterized in that: The invention comprises the following raw materials in parts by weight: 180-220 parts of clasentan sodium, 10-25 parts of antioxidant, 3-8 parts of osmotic pressure regulator, 400-500 parts of cosolvent, and the balance is water for injection.

2. The clasentan sodium injection according to claim 1, characterized in that: The antioxidant is at least one of sodium thiosulfate, vitamin C and sodium sulfite.

3. The clasentan sodium injection according to claim 1, characterized in that: The osmotic pressure regulator is at least one of glucose, sodium chloride, phosphate or citrate.

4. The clasentan sodium injection according to claim 1, characterized in that: The cosolvent is one of polyethylene glycol, propylene glycol and starch slurry.

5. The clasentan sodium injection according to claim 1, characterized in that: The raw materials of the clasentan sodium injection also include 10-25 parts of an acid-base regulator and 5-12 parts of a stabilizer. The acid-base regulator adjusts the pH of the clasentan sodium injection to 7-9.

6. The clasentan sodium injection according to claim 5, characterized in that: The acid-base regulator includes an acid regulator and an alkali regulator, the acid regulator is at least one of phosphoric acid, citric acid, tartaric acid, oxalic acid, and malic acid, and the alkali regulator is at least one of sodium phosphate, disodium hydrogen phosphate, sodium citrate, and sodium tartrate.

7. The clasentan sodium injection according to claim 5, characterized in that: The stabilizer is hydroxypropyl-β-cyclodextrin.

8. A method for preparing the clasentan sodium injection according to any one of claims 1 to 7, characterized in that: The method comprises the following specific steps: mixing deoxygenated injection water with clasentan sodium and a solvent, stirring evenly, then stirring evenly an antioxidant and an osmotic pressure regulator, filtering with a composite filter membrane, and then filling and sterilizing by hot pressing to obtain clasentan sodium injection.

9. The method for preparing clasentan sodium injection according to claim 8, characterized in that: The deoxygenated water for injection is mixed with clasentan sodium and a cosolvent, and stirred evenly. Then, an antioxidant, an osmotic pressure regulator, and a stabilizer are stirred evenly to form a clasentan sodium mixture. The pH of the clasentan sodium mixture is adjusted to 7-9 with an acid-base regulator, and the mixture is filtered with a composite filter membrane, and then filled and sterilized by hot pressing to obtain clasentan sodium injection.

10. The method for preparing clasentan sodium injection according to claim 8, characterized in that: The composite filter membrane comprises a filter membrane with a pore size of 0.4-0.6 μm and a filter membrane with a pore size of 0.1-0.3 μm.